Abstract

Pulse wave velocity (PWV), a direct marker of arterial stiffness, is an independent
cardiovascular risk factor. Although the angiotensin II type 1 receptor blockade belongs
to major antihypertensive and cardioprotective therapies, less is known about the
effects of long-term stimulation of the angiotensin II type 2 receptor. Previously,
compound 21, a selective nonpeptide angiotensin II type 2 receptor agonist improved
the outcome of myocardial infarction in rats along with anti-inflammatory properties.
We investigated whether compound 21 alone or in combination with angiotensin II type
1 receptor blockade by olmesartan medoxomil could prevent PWV increase and aortic
remodeling in N(ω)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension. Male
adult Wistar rats (n=65) were randomly assigned to control, L-NAME, L-NAME+compound-21,
L-NAME+olmesartan, and L-NAME+olmesartan+compound-21 groups and treated for 6 weeks.
We observed that L-NAME hypertension was accompanied by enhanced PWV, increased wall
thickness, and stiffness of the aorta, along with elevated hydroxyproline concentration.
Olmesartan completely prevented hypertension, PWV and wall thickness increase, and
the increase of aortic stiffness and partly prevented hydroxyproline accumulation.
Compound 21 partly prevented all of these alterations, yet without concomitant prevention
of blood pressure rise. Although the combination therapy with olmesartan and compound
21 led to blood pressure levels, PWV, and wall thickness comparable to olmesartan-alone-treated
rats, only in the combination group was complete prevention of increased hydroxyproline
deposition achieved, resulting in even more pronounced stiffness reduction. We conclude
that chronic angiotensin II type 2 receptor stimulation prevented aortic stiffening
and collagen accumulation without preventing hypertension in rats with inhibited NO
synthase. These effects were additive to angiotensin II type 1 receptor blockade,
yet without additional blood pressure-lowering effect, and they seem to be NO and
blood pressure independent.